Thiophene ethanolamines

ABSTRACT

Thiophene ethanolamines substituted on the nitrogen atom with an alkyl or aralkyl radical and optionally substituted on the thiophene portion, are disclosed. The thiophene ethanolamines possess antihypertensive and β-receptor blocking activities. Methods for their preparation and use are given.

This is a division of application Ser. No. 569,509, filed Apr. 18, 1975,now U.S. Pat. No. 4,024,156, granted May 17, 1977.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to thiophene ethanolamines, to processes fortheir preparation and to intermediates therefor.

More specifically, the compounds of this invention are thiopheneethanolamines characterized further in that they are substituted on thenitrogen atom with an alkyl or an aralkyl radical and are optionallysubstituted on the thiophene portion.

(B) Description of the Prior Art

The prior art relating to thiophene ethanolamines is rather niggardly.An early report by C. F. Heubner, et al., J. Org. Chem., 18, 21 (1953),described the preparation of the thiophene ethanolamine,α-(aminomethyl)thiophene-2-methanol, which was found to have pressoractivity. In 1968, E. D. Bergmann and Z. Goldschmidt, J. Med. Chem., 11,1121 (1968), described some corresponding N-alkyl derivatives of thelatter thiophene ethanolamine, noting that these derivatives possessedno significant pharmacologic activity. A still more recent report, C.Carrol, et al., J. Med. Chem., 16, 882 (1973), described a relatedseries of N-substituted thiophene ethanolamines, the substitution beingalkyl, phenyl or such that the nitrogen atom forms part of apyrrolidine, piperidine or morpholine ring. A variety of pharmacologicproperties were reported for the series including the property that theyantagonized the hypotensive response to isoproterenol.

Unexpectedly, we have found that the compounds of the present invention,and particularly the N-(aralkyl)-thiophene ethanolamines are potentantihypertensive and β-receptor blocking agents. These propertiestogether with their relatively low toxicity and the direct manner inwhich these compounds are prepared render them useful and practical forthe treatment of hypertensive conditions and lessening undersirableβ-adrenergic stimulation of the myocardium.

SUMMARY OF THE INVENTION

The thiophene ethanolamines of this invention are represented generallyby the formula ArCHOR¹ CHR² NR³ R⁴ in which Ar is the radical ##STR1##wherein X¹, X² and X³ are selected from the group consisting ofhydrogen, halo, lower alkyl, lower alkoxy and phenyl; R¹ is hydrogen orlower alkyl, R² is hydrogen or lower alkyl; R³ is hydrogen or loweralkyl; and R⁴ is lower alkyl, 2-indol-3-ylethyl or a phenethyl radicalof the formula, ##STR2## wherein R⁵ is hydrogen or lower alkyl, R⁶ ishydrogen or hydroxy and R⁷, R⁸ and R⁹ are the same or different selectedfrom the group consisting of hydrogen, lower alkyl, lower alkoxy,hydroxy and halo, or R⁶ and R⁷ are joined to form a methylenedioxyradical and R⁸ is hydrogen; or R³ and R⁴ together with the nitrogen towhich they are joined form a 4-phenyl-, 4-(4-methoxyphenyl)- or4-(o-tolyl)-piperazin-1-yl group with the proviso that when Ar is theradical ##STR3## wherein X¹, X² and X³ are selected from the groupconsisting of hydrogen or halo, R⁴ is other than lower alkyl as definedherein; and by the formula ArCH(CHR² OH)NR³ R⁴ in which AR, R², R³ andR⁴ are as defined herein.

The preferred ethanolamines of this invention are represented by theformula

    ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4

in which Ar is selected from the group consisting of 2-thienyl, 5-(loweralkyl)-2-thienyl, 5-phenyl-2-thienyl and 4,5-dichloro-2-thienyl; R¹ ishydrogen or lower alkyl; R² is hydrogen or lower alkyl; R³ is hydrogenor lower alkyl; and R⁴ is 2-indol-3-ylethyl, a substituted phenethyl ofthe formula ##STR4## wherein R⁵ is hydrogen or lower alkyl, R⁶ ishydrogen or hydroxy and R⁷, R⁸ and R⁹ are the same or different selectedfrom the group consisting of hydrogen, lower alkyl, lower alkoxy,hydroxy and halo or R⁷ and R⁸ are joined to form a methylenedioxyradical and R⁹ is hydrogen; or R³ and R⁴ together with the nitrogen towhich they are joined form a 4-(4-methoxyphenyl)- or4-(o-tolyl)-piperazin-1-yl group; and by the formula ArCH(CHR² OH)NR³ R⁴in which Ar, R², R³, and R⁴ are as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radicals containing from three to four carbon atoms and includesmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl, hexyland the like.

The term "lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy, t-butoxy and the like.

The term "halo" as used herein contemplates halogens and includeschlorine, bromine and iodine.

The term "alkanoyl" as used herein contemplates the radical COCH₂ R² inwhich R² is hydrogen or lower alkyl as defined herein.

The compounds of this invention form salts with pharmaceuticallyacceptable acids. Such acid additions salts are included within thescope of this invention.

The acid addition salts are prepared by reacting the corresponding baseform of the thiophene ethanolamine with at least one equivalent, orpreferably with an excess of the appropriate acid in an organic solvent,for example, ether or an ethanol-ether mixture. These salts, whenadministered to mammals, possess the same pharmacologic activities asthe corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, oxalate, maleate, citrate, hydrobromide andhydrochloride. Both the base compounds and the salts have the distinctadvantage of possessing a relatively low order of toxicity.

The stereochemical isomers of the compounds of this invention, madepossible by the occurrence of asymmetric centers contained therein, arealso included within the scope of this invention.

The antihypertensive effect of the compounds of this invention and theiracid addition salts is demonstrated in standard tests, for example, intests conducted in the spontaneously hypertensive rat such as describedby I. Vavra, et al., Can. J. Physiol. Pharmacol., 51 727 (1973). Forinstance, the following compounds have been found to be active in thistest at 50 mg/kg or less when they are given by gavage as a single dose.

α-{[3,4-dimethoxyphenethyl)amino]methyl}-2-thiophenemethanol oxalate(Example 15),

α-{[3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanoloxalate (Example 16), and

α-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-phenyl-2-thiophenemethanolhydrochloride (Example 19).

Thus an embodiment of this invention includes the method of loweringblood pressure in a hypertensive host such as a mammal by administeringa therapeutically effective amount of the compounds of this invention tothe host.

The β-receptor blocking activity of the compounds and their acidaddition salts is demonstrated also in standard tests such as thosedescribed by E. Westermann and K. Stock in "International Symposium onDrugs Affecting Lipid Metabolism, 3rd, Milan, 1968", W. J. Holmes, etal., Ed., Plenum Press, New York, 1969, pp 45 - 61.

When the compounds of this invention and their acid addition salts areemployed as antihypertensive or β-receptor blocking agents inwarm-blooded mammals, e.g. rats and mice, they are used alone or incombination with pharmacologically acceptable carriers. The proportionof the compound is determined by its solubility and chemical nature,chosen route of administration and standard biological practice. Forexample, they are administered orally in solid form containing suchexcipients as starch, milk sugar, certain types of clay and so forth.They may also be administered orally in the form of solutions or theymay be injected parenterally. For parenteral administration they areused in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstance is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in a range of from about 0.1 mg to about 100 mg per kiloper day, although as aforementioned variations will occur. However, adosage level that is in the range of from about 5.0 mg to about 50 mgper kilo per day is most desirably employed in order to achieveeffective results. Process

One method for preparing the compounds of this invention is illustratedas follows:

    Ar--H → ArCOCH.sub.2 R.sup.2 → ArCOCHR.sup.2 Y → ArCHOHCHR.sup.2 Y → ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4

in which R¹ is hydrogen, Y is bromo, chloro or iodo and Ar, R², R³ andR⁴ are as defined herein.

The requisite starting materials of formula Ar--H are either known orare prepared readily by known methods. Examples of the known thiophenestarting materials include the commercially available 2-chlorothiopheneand 2-bromothiophene. 2,3-Dibromothiophene is described by S. O.Lawesson, Arkiv. Kemi, 11, 378 (1957), 3,4-dibromothiophene is describedby S. Gronowitz, Acta Chem. Scand., 13, 1045 (1959),2,3-dichlorothiophene, 3,4-dichlorothiophene are described by Corral, etal., cited above, 2-methoxythiophene is described by J. Sice, J. Amer.Chem. Soc., 75, 3697 (1953), 3,4-dimethoxy thiophene is described by E.W. Fager, J. Amer. Chem. Soc., 67, 2217 (1945), 2-methylthiophene isdescribed by F. S. Fawcett, J. Amer. Chem. Soc., 68, 1420 (1946) and2-phenylthiophene is described by A. I. Kosak, et al., J. Amer. Chem.Soc., 76, 4450 (1954).

General methods for making any of the halo, alkyl, alkoxy, and arylthiophenes of formula Ar--H are described in general textbooks; forexample, Rodd's Chemistry of Carbon Compounds, 2nd ed., S. Coffey, Ed.,Vol. IV-A, Elsevier Scientific Publishing Co., Amsterdam, 1973 pp 220 -255 and "Heterocyclic Compounds", R. C. Elderfield, Ed., Vol. 1, JohnWiley & Sons, Inc., New York and London, 1950, pp 208 - 276.

With reference to the process the thiophene starting materials offormula Ar--H are subjected to acylation to give the corresponding2-acylthiophene derivatives of formula ArCOCH₂ R² in which Ar and R² areas defined above. Although a variety of methods are reported foraccomplishing this acylation, see for example the aforementionedtextbooks, a preferred method for obtaining the 2-acylthiophenederivatives of formula ArCOCH₂ R² in which R² is hydrogen or lower alkylinvolves treating the appropriate thiophene of formula Ar--H with anappropriate alkanoyl chloride or bromide, for example, acetyl chlorideor propionyl bromide, in an inert organic solvent, preferably benzene ortoluene, at temperatures ranging from -20° to 80° C, preferably 0° to30° C for 2 to 72 hours, preferably 6 to 72 hours.

Alternatively, the 2-acylthiophenes are prepared from the appropriatethiophene of formula Ar--H according to a modification of the method ofW. Steinkopf and W. Kohler, Justus Liebigs' Ann. Chem., 532, 250 (1937).The latter method involves treating the thiophene with an organiclithium reagent, preferably n-butyl lithium in an inert solvent,preferably tetrahydrofuran, ether, hexane and the like, to generate thecorresponding 2-thienyl lithium derivative. The latter derivative isreacted with carbon dioxide to give the corresponding 2-thiophenecarboxylic acid which on treatment with the appropriate lower alkyllithium gives the desired 2-acylthiophene.

A number of the 2-acylthiophenes utilized in the process of thisinvention are known; for example, 2-acetylthiophene described by J. R.Johnson and G. E. May, Org. Synth., 18, 1 (1938); 2-propionylthiophene,described by H. A. Bruson and T. W. Riener, J. Amer. Chem. Soc. 70, 214(1948) and 2-acetyl-3,4-dichlorothiophene described by E. Profft and G.Solf, J. Prakt. Chem., 24, 38 (1964). See also the general textbooksnoted above.

In the next step the 2-acylthiophene is converted by halogenation to thecorresponding haloketone of formula ArCOCHR² Y in which R² is hydrogenor lower alkyl and Y is bromo, chloro or iodo. This conversion isaccomplished readily by halogenating agents known to be effective forintroducing a halogen atom α to a ketone. In a preferred embodiment ofthis conversion the halogenation is effected with substantially anequimolar amount of elemental bromine, pyridumium bromide or cupricbromide in an inert organic solvent, preferably chlor form or aceticacid, to obtain the corresponding bromoketone, ArCOCHR² Br. Similarconversions to the corresponding chloroketone or iodoketone areaccomplished with elemental chlorine or iodine, respectively. In thesecases the halogenation proceeds readily. Convenient times andtemperatures include 10 to 60 minutes and 0° to 30° C.

Several of the haloketones of formula ArCOCHR² Y have been describedpreviously; for example 2-(bromoacetyl)thiophene, described by Heubner,et al., cited above, 2-(chloroacetyl)thiophene, described by W. S.Emerson and T. M. Patrick, J. Org. Chem., 13, 724 (1948) and2-(chloroacetyl)-3,4-dichlorothiophene, described by Profft and Solf,cited above.

In the next step the α-haloketone of formula ArCOCHR² Y in which Ar, R²and Y are as defined herein is reduced with a complex metal hydride togive the corresponding halohydrin of formula ArCHOHCHR² Y. Examples ofsuitable complex metal hydrides for this reduction are sodiumborohydride, lithium aluminium hydride and diborane. Sodium borohydrideis preferred. The reduction is carried out in a non-reactive solventmedium. When sodium borohydride is used, preferred solvents includemethanol or tetrahydrofuran. When lithium aluminum and diborane are usedas the reducing agent, preferred solvents include the non-hydroxylicsolvents, for example, diethyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane and the like. Generally the reaction is bestperformed at temperatures ranging from 0° to 40° C for periods varyingfrom 30 minutes to 24 hours. While equivalent quantities of reactantsmay be used, it is preferable to use the reducing agent in moderateexcess.

The halohydrin so obtained is used thereafter for N-alkylation of theappropriate primary or secondary amine of formula NHR² R⁴ to obtain thecorresponding thiophene ethanolamine of formula ArCHOR¹ CHR² NR³ R⁴ inwhich R¹ is hydrogen and R², R³ and R⁴ are as defined herein. One methodfor effecting this N-alkylation includes bringing the reactants togetherin the presence of a base; suitable bases for this purpose are alkalimetal carbonates and alkali metal bicarbonates. The ratio of reactantswill depend on the starting material that is employed and the productthat is desired. When the starting material is a primary amine, asecondary amine product is obtained by using slightly more than oneequivalent of alkylating agent and base, whereas a tertiary amineproduct is obtained by using somewhat more than two equivalents ofalkylating agent and base. When the starting material is a secondaryamine, a tertiary amine product is obtained by using slightly more thanone equivalent of alkylating agent and base. Depending upon theparticular alkylating agent and base chosen, a variety of solvents andreaction conditions may be used. Some examples of suitable solvents arearomatic hydrocarbons, ethers, lower alkanols, lower aliphatic ketones,and other non-reactive solvents, such as dimethyl sulfoxide,N,N-dimethylformamide, and and acetonitrile. The temperature andduration of the reaction are not critical and may be varied over a widerange, depending upon the particular alkylating agent and solvent thatare used. Generally it is most convenient and efficacious to carry outthe reaction at the reflux temperature of the reaction mixture for aperiod of 1 hour to several days.

The requisite primary and secondary amines of formula NHR³ R⁴ are eitherknown or are prepared by known methods; for example, see "Methoden derOrganic Chemie", (Houben-Weyl), E. Muller, Ed., Vol. 11/1, Georg ThiemeVerlag, Stuttgart, 1957, pp 9 - 1033.

Using similar N-alkylation conditions any of the aforementionedsecondary amines (i.e., compounds of formula ArCHOR¹ CHR² NR³ R⁴ inwhich R³ is hydrogen) are converted to corresponding tertiary amines.Preferred conditions include treating the secondary amine with about 5to 10 molar equivalents of the appropriate lower alkyl halide or aralkylhalide in an inert organic solvent, for instance, ethanol,tetrahydrofuran or benzene, from 1 to 24 hours or more at a temperatureranging from about 20° - 80° C.

In a preferred embodiment of the process the N-alkylation is effected byheating the bromohydrin with 1.0 to 1.5 molar equivalents of the primaryor secondary amine either together in a pressurized container at 80° -120° C or at 40° to 120° C in the presence of an inert organic solvent.Generally the reactants are heated together for 3 to 24 hours. Preferredsolvents for this latter conditions include benzene, toluene, dioxaneand tetrahydrofuran.

It should be noted that in the aforementioned N-alkylation reactions, aby-product is sometimes encountered. This by-product is isomeric to theexpected thiophene ethanol and has the general formula ArCH(CHR² OH)NR³R⁴ in which Ar, R², R³ and R⁴ are as defined herein. These isomers alsopossess useful antihypertensive properties as demonstrated in the abovetests. Accordingly, these isomers and their corresponding acid additionsalts with pharmaceutically acceptable acids can be formulated and usedfor this purpose in the manner described above for the thiopheneethanolamines.

In the case where the thiophene ethanolamines of this invention are thecompounds of formula ArCHOR¹ CHR² NR³ R⁴ in which R¹ and R² arehydrogen, R³ and R⁴ are as defined herein and Ar is the radical ##STR5##wherein X¹, X² and X³ are selected from the group of hydrogen and loweralkoxy with the proviso that at least one of X¹, X² or X³ is loweralkoxy, the following alternative procedure has been found to beconvenient: ##STR6## in which X¹, X² and X³ are as defined in the lastinstance and R³ and R⁴ is as defined herein.

With reference to this latter process the substituted thiophene offormula 1 is reacted with a organolithium reagent in an inert solvent.Suitable organolithium reagents include n-butyl lithium, n-propyllithium, phenyl lithium and the like. Suitable inert solvents includeether, tetrahydrofuran, hexane and the like. In this manner thecorresponding thienyl lithium derivative is generated. The lithiumderivative is then reacted with a dialkyl oxalate, preferably dimethyloxalate, to give the corresponding ester of formula 2 in which R¹⁰ islower alkyl, preferably methyl. This ester is then hydrolyzed with astrong base, for example, sodium or potassium hydroxide, in the presenceof sufficient water to effect hydrolysis. The hydrolysis is performedusing a suitable solvent, for example, methanol or ethanol. The reactionmixture is maintained at a temperature of from 25° C to the refluxtemperature of the mixture until hydrolysis occurs, usually from 10minutes to 6 hours is sufficient. The reaction mixture is then renderedacidic with an acid, for example, acetic acid, hydrochloric acid,sulfuric acid and the like, and the free acid (compound 3) isolated.

At this point the latter free acid is subjected to amidation. Thisamidation is accomplished readily by first treating the acid with alower alkyl chloroformate, preferably ethyl chloroformate, in thepresence of triethylamine, to afford the corresponding mixed anhydride.Reaction of the mixed anhydride with the appropriate amine of formulaHNR³ R⁴ gives the corresponding amide of formula 4.

Thereafter, treatment of the latter amide with a suitable complex metalhydride yields the corresponding desired thiophene ethanolamine offormula 5. Examples of suitable complex metal hydrides are lithiumaluminum hydride, aluminum hydride-aluminum chloride, diborane andsodium borohydride-aluminum chloride; lithium aluminum hydride beingpreferred.

In a special modification of the latter step the amide of formula 4 inwhich R³ is hydrogen is first treated with triethyloxonium fluoroboratein an inert organic solvent, for example, chloroform or methylenedichloride, to give the intermediate iminoether fluoroborate. Subsequentreduction of the latter intermediate with an alkali metal borohydride,preferably sodium borohydride, give the corresponding desired thiopheneethanolamine of formula 5 in which R³ is hydrogen.

Finally, in the case where it is desired to obtain the thiopheneethanolamines of formula ArCHOR¹ CHR² NR³ R⁴ in which R¹ is lower alkyl(i.e., R¹ forms part of a lower alkoxy group), the preferred mode ofpreparation involves a modification of the above process in which thehalohydrin of formula ArCHOHCHR² Y in which Ar, R² and Y are as definedherein is treated with the appropriate lower alkanol in the presence ofan acid catalyst, for example, p-toluenesulfonic acid, sulfuric acid orboron trifluoride etherate, to give the corresponding lower alkoxyderivative of formula ArCHOR¹ CHR² Y in which Ar, R² and Y are asdefined herein and R¹ is lower alkyl. Conversion of the latter compoundto the corresponding amine in the same manner described hereinbeforegives the thiophene ethanolamines of this invention of formula ArCHOR¹CHR² NR³ R⁴ in which Ar, R², R³ and R⁴ are as defined herein and R¹ islower alkyl.

The following examples illustrate further this invention.

EXAMPLE 1 Acylation -- Method A

By following the procedure described by J. R. Johnson and G. E. May,Org. Synth, 18, 1 (1938), for the preparation of 2-acetylthiophene, thefollowing 2-acylthiophenes are obtained:

2-acetyl-5-bromothiophene, mp 94° - 95° C from 2-bromothiophene andacetyl chloride;

2-acetyl-5-chlorothiophene, mp 46° C, from 2-chlorothiophene and acetylchloride;

2-acetyl-3,4-dibromothiophene, mp 80° - 81° C, from 3,4-dibromothiopheneand acetyl chloride;

2-acetyl-4,5-dibromothiophene, mp 84° - 85° C, from 2,3-dibromothiopheneand acetyl chloride;

2-acetyl-3,4-dichlorothiophene, mp 51° - 52° C, from3,4-dichlorothiophene and acetyl chloride;

2-acetyl-4,5-dichlorothiophene, mp 66° - 67° C, from2,3-dichlorothiophene and acetyl chloride;

2-acetyl-3,4-dimethoxythiophene, mp 102° C, from 3,4-dimethoxybenzeneand acetyl chloride;

5-chloro-2-propionylthiophene, mp 50° - 51° C, from 2-chlorothiopheneand propionyl chloride;

2-acetyl-5-methylthiophene, nmr (CDCl₃) δ 2.50 (s, 3H), 2.55 (s, 3H),6.83 (m, 1H), 7.57 (d, 1H), from 2-methylthiophene and acetyl chloride;and

2-acetyl-5-phenylthiophene, mp 115° C, from 2-phenylthiophene and acetylchloride.

EXAMPLE 2 Acylation -- Method B

Another method for preparing 2-acylthiophenes is exemplified by thefollowing preparation of 2-acetyl-5-phenylthiophene:

A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydroustetrahydrofuran (THF) is treated dropwise with a solution of n-butyllithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture isstirred for 1 hr. The resulting black solution is poured onto 50 g ofsolid CO₂ covered with ether. When all the CO₂ is evaporated, themixture is treated with 200 ml of water, acidified with 10% HCL andextracted with ether. The extract is washed with 5% NaOH. The latterwashings are cooled and rendered acidic with 20% HCL. The resultingprecipitate is collected and recrystallized from 1000 ml CCL₄ to give5-phenyl 2-thiophenecarboxylic acid, mp 180° C, γ_(max) ^(CHCl).sbsp.31665 cm⁻¹, as yellow green crystals.

The latter compound (16.7 g, 0.08 mole) in 300 ml of anhydrous ether iscooled to -50° C and treated dropwise with methyl lithium (0.16 mole) inether (IM solution). The mixture is allowed to warm to 0° C over aperiod of 2 hr. Thereafter the mixture is poured onto cold 5% HCl andextracted with ether. The extract is washed with 5% NaHCO₃, water andbrine, dried (MgSO₄) and concentrated to give a yellow solid which ispurified by chromatography on silica gel to give pure2-acetyl-5-phenylthiophene, mp 115° C, γ_(max) ^(CHCl).sbsp.3 1650 cm,identical to the product of the same name described in Example 1.

Other 2-acylthiophenes are obtained by this procedure by utilizing theappropriate thiophene of formula Ar--H; for example, the use of2,3-dichlorothiophene gives 2-acetyl-4,5-dichlorothiophene.

EXAMPLE 3 Halogenation

The haloketones are obtained by procedures which are exemplified asfollows:

Method A

a solution of 2-acetyl-5-phenylthiophene (11.7 g, 0.058 mole), describedin Examples 1 and 2, in 100 ml of glacial acetic acid is treateddropwise with bromine (9.3 g, 0.058 mole). The mixture is stirred for1/2 hr, poured into cold water and extracted with chloroform. Theextract is washed with water, 5% NaHCO₃ and brine, dried (K₂ CO₃) andconcentrated to give a yellow solid. The solid is subjected tochromatography on silica gel to give bromomethyl 5-phenyl-2-thienylketone (ArCOCHR² Y; Ar is 5-phenyl-2-thienyl, R² = H and Y = Br); mp114° C.

Method B

a solution of 5-methyl-2-thienyl methyl ketone (24.8 g, 0.177 mole),described in Example 1, in 170 ml chloroform is treated with pyridiniumbromide perbromide (56.7 g, 0.177 mole). The mixture is stirred for 21/2hr. The resulting deep red solution is poured into ice water. Themixture is extracted with ether. The extract is washed with water andbrine, dried (MgSO₄), and concentrated to give a brown liquid. The oilis purified by chromatography on silica gel to givebromomethyl-5-methyl-2-thienyl ketone (ArCOCHR² Y; Ar is5-methyl-2-thienyl, R² = H and Y = Br); γ_(max) ^(film) 1650 cm⁻¹, nmr(CDCl₃) δ 2.58 (s, 3H), 4.3 (s, 2H), 6.86 (m, 1H), 7.67 (m, 2H).

Method C (method of L. C. King and G. K. Ostrum, J. Org. Chem., 29, 3459(1964)

A stirred suspension of cupric bromide (20.7 g) in 50 ml ethyl acetateis heated to reflux. 2-Acetylthiophene (7.0 g) dissolved in 50 mlchloroform is added rapidly from a dropping funnel. The reaction mixtureis heated further with vigorous stirring until the black cupric bromidehad all been converted to the white cuprous bromide (about 2 hr.). Thereaction mixture is cooled, filtered and concentrated. The resulting oilis subjected to chromatography on silica gel. Evaporation of the eluant(benzene-hexane, 8:2) gives bromomethyl 2-thienyl ketone (ArCOCHR² Y; Aris 2-thienyl, R² = H and Y = Br); bp 100° C/0.2mm, γ_(max)^(CHCl).sbsp.3 1660, 1410 cm³¹ 1.

The following table lists other haloketones prepared by either method A,B or C, as indicated, together with the requisite starting materialsdescribed in Example 1.

    __________________________________________________________________________    STARTING MATERIAL                                                                            METHOD                                                                              HALOKETONE                                               __________________________________________________________________________    2-acetyl-5-bromothiophene                                                                    A     bromomethyl 5-bromo-2-                                                        thienyl ketone, mp 90 - 91° C                     2-acetyl-5-chlorothiophene                                                                   B     bromomethyl 5-chloro-2-                                                       thienyl ketone, mp 72 - 73° C                     2-acetyl-3,4-dibromothiophene                                                                C     bromomethyl 3,4-dibromo-                                                      2-thienyl ketone,                                                             mp 80 - 82° C                                     2-acetyl-4,5-dibromothiophene                                                                A     bromomethyl 4,5-dibromo-2-                                                    thienyl ketone, mp 67.5 -                                                     70° C                                             2-acetyl-3,4-dichlorothiophene                                                               C     bromomethyl 3,4-dichloro-                                                     2-thienyl ketone, mp 46 -                                                     47° C                                             2-acetyl-4,5-dichlorothio-                                                                   B     bromomethyl 4,5-dichloro-                                phene                2-thienyl ketone,                                                             γ.sub.max .sup.CHCl.sbsp.3 1665, 1520, 1405                             cm.sup.-1                                                2-acetyl-3,4-dimethoxythio-                                                                  B and C                                                                             bromomethyl 3,4-dimethoxy-                               phene                2-thienyl ketone,                                                             γ.sub.max .sup.CHCl.sbsp.3 3120, 1650                                   cm.sup.-1 ;                                                                   bromomethyl 5-bromo-                                                          3,4-dimethoxy-2-thienyl                                                       ketone, mp 94° C, isolated                                             as a by-product (separated                                                    by chromatography) when                                                       method C is used.                                        5-chloro-2-propionyl-                                                                        B     1-bromoethyl 5-chloro-2-                                 thiophene            thienyl ketone,                                                               γ.sub.max .sup.CHCl.sbsp.3 1660, 1410              __________________________________________________________________________                         cm.sup.-1                                            

EXAMPLE 4 Reduction

A solution of the haloketone, bromomethyl 2-thienyl ketone (6.0 g),described in Example 3, in 40 ml of methanol is cooled to 0° C. Sodiumborohydride (1.11 g) in 10 ml of methanol is added rapidly to thesolution. After 15 minutes the reaction mixture is diluted withice-water and extracted with ether. The extract is washed with water andbrine, dried (MgSO₄) and concentrated to giveα-(bromomethyl)-2-thiophenemethanol; γ_(max) ^(CHCl).sbsp.3 3550, 3400,1060, 1035 cm⁻¹ (ArCHOHCHR² Y; Ar = 2-thienyl, R² = H and Y = Br).

By following the procedure of Example 4 and using the appropriatehaloketone as starting material the other corresponding halohydrins offormula ArCHOHCHR² Y are obtained. Examples of such halohydrins arelisted in the following table together with the requisite startingmaterial described in Example 3.

    __________________________________________________________________________    EXAMPLE                                                                              STARTING MATERIAL                                                                           HALOHYDRIN                                               __________________________________________________________________________     5     bromomethyl 5-bromo-2-                                                                      α-(bromomethyl)-5-bromo-2-                                thienyl ketone                                                                              thiophenemethanol,                                                            γ.sub.max .sup.CHCl.sbsp.3 3540, 3400 cm            6     bromomethyl 5-chloro-2-                                                                     α-(bromomethyl)-5-chloro-2-                               thienyl ketone                                                                              thiophenemethanol,                                                            γ.sub.max .sup.CHCl.sbsp.3 3570, 3350, 1062,                            1000 cm.sup.-1                                            7     bromomethyl 3,4-dibromo-                                                                    α-(bromomethyl)-3,4-dibromo-                              2-thienyl ketone                                                                            2-thiophenemethanol,                                                          γ.sub.max .sup.CHCl.sbsp.3 3560, 3350 cm            8     bromomethyl 4,5-dibromo-                                                                    α-(bromomethyl)-4,5-                                      2-thienyl ketone                                                                            dibromo-2-thiophenemethanol,                                                  γ.sub.max .sup.CHCl.sbsp.3 3570, 3300                                   cm.sup.-1                                                 9     bromomethyl 3,4-dichloro-                                                                   α-(bromomethyl)-3,4-dichloro-                             2-thienyl ketone                                                                            2-thiophenemethanol,                                                          γ.sub.max .sup.CHCl.sbsp.3 3575, 3350, 3120,                            1345, 1075 cm.sup.-1                                     10     bromomethyl 3,4-dichloro-                                                                   α-(bromomethyl)-4,5-dichloro-                             2-thienyl ketone                                                                            2-thiophenemethanol,                                                          γ.sub.max .sup.CHCl.sbsp.3 3570, 3350, 1540,                            1040 cm.sup.-1                                           11     bromomethyl 3,4-dimethoxy-                                                                  α-(bromomethyl)-3,4-dimethoxy-                            2-thienyl ketone                                                                            2-thiophenemethanol,                                                          γ.sub.max .sup.CHCl.sbsp.3 3560, 3400, 3130                             cm.sup.-1                                                12     1-bromoethyl 5-chloro-                                                                      α-(1-bromoethyl)-5-chloro-2-                              2-thienyl ketone                                                                            thiophenemethanol                                        13     bromomethyl 5-methyl                                                                        α-(bromomethyl)-5-methyl-2-                               2-thienyl ketone                                                                            thiophenemethanol, nmr (CDCl.sub.3)                                           δ 2.47 (m, 4H), 3.6 (m, 2H),                                            5.0 (m, 1H), 6.8 (m, 2H)                                 14     bromomethyl 5-phenyl-                                                                       α-(bromomethyl)-5-phenyl-2                                2-thienyl ketone                                                                            thiophenemethanol, nmr (CDCl.sub.3)                                           δ 2.75 (1H), 3.65 (m, 2H),                                              5.1 (m, 1H), 6.9 - 7.65 (m, 7H)                          __________________________________________________________________________

EXAMPLE 15 α-{[(3,4-Dimethoxyphenethyl)amino]methyl}-2-thiophenemethanol(ArCHOR¹ CHR² NR³ R⁴ ; Ar = 2-thienyl, R¹, R² and R³ = H and R⁴ =3,4-dimethoxyphenethyl)

A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (11.4g, 0.055 mole), described in Example 4, and the primary amine,3,4-dimethoxyphenethylamine (15 g, 0.083 mole), in 200 ml toluene isheated at reflux for 12 hr. The mixture is cooled to 25° C, shaken with10% NaOH and the layers separated. The aqueous layer is extracted withchloroform and the combined organic phases washed with water and brine,dried (K₂ CO₃) and concentrated. The resulting dark brown oil ispurified by chromatography on silica gel to give the title compound asan oil; nmr (CDCl₃) 2.9 (m, 6H), 3.45 (2H), 3.85 (s, 6H), 5.05 (m, 1H),6.7 - 7.3 (m, 6H).

The oxalic acid addition salt (oxalate) of the title compounds has mp154° - 155° C.

EXAMPLE 16α-{[(3,4-Dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol(ArCHOR¹ CHR² NR³ R⁴ ; Ar = 5-methyl-2-thienyl, R¹, R² and R³ = H and R⁴= 3,4-dimethoxyphenethyl)

A solution of the halohydrin, α-(bromomethyl)-5-methyl-2-thienylmethanol(5.0 g, 0.0226 mole), described in Example 13, and the primary amine,3,4-dimethoxyphenethylamine (6.2 g, 0.0339 mole), in 30 ml of dioxane isheated at reflux for 3 hr. The mixture is cooled to room temperature,diluted with 200 ml of chloroform and shaken with 10% NaOH. The organicphase is separated and washed with water and brine, dried (K₂ CO₃) andconcentrated to give a light brown oil. The concentrate is subjected tochromatography on silica gel using methanol-chloroform (1:9) as theeluant. Concentration of the first fractions affordsβ-(3,4-dimethoxyphenethylamino)-5-methyl-2-thienylethanol; nmr (CDCl₃) δ2.27 (s, 2H), 2.47 (s, 3H), 2.8 (m, 3H), 3.7 cm, 2H), 3.87 (s, 6H) and6.75 (m, 5H), an isomer of the title compound; the oxalic acidaddition.salt of this isomer having mp 108° - 110° C. Concentration ofthe following second fractions affords the title compound; nmr (CDCl₃) δ2.45 (s, 3H), 3.0 (m, 6H), 3.85 (s, 6H), 4.45 (2H), 5.1 (t, J = 6, 2H),6.8 (m, 5H); the oxalic acid addition salt thereof having mp 160° C.

By following the procedures of Examples 15 and 16 and using theappropriate halohydrin and the appropriate primary or secondary amine,other thiophene ethanolamines of this invention are obtained. Examplesof such thiophene ethanolamines are listed in the following tabletogether with the requisite starting materials. The halohydrin startingmaterials are noted by the example in which they are prepared.

    __________________________________________________________________________           WHICH HALOHYDRIN                                                                           AMINE OF   THIOPHENE ETHANOLAMINE                         EXAMPLE                                                                              IS PREPARED  FORMULA NHR.sup.3 R.sup.4                                                                OF FORMULA ArCHOHCHR.sup.2 NR.sup.3            __________________________________________________________________________                                   R.sup.4                                        17     4            1-(o-tolyl)-                                                                             α-(2-thienyl)-4-(o-tolyl)-1-                                 piperazine piperazineethanol; mp 81 - 96° C;                                      nmr                                                                           (CDCl.sub.3) δ 2.3 (s, 3H), 2.9                                         (m, 10H), 4.0 (broad s, 1H),                                                  5.1 (t, J = 7, 1H), 7.2 (m, 7H);                                              the hydrochloric acid addition                                                salt (hydrochloride) has mp 221° C      18     13           3,4-(methylene-                                                                          5-methyl-α-{[3,4-(methylenedioxy)                            dioxy)phenethyl-                                                                         phenethyl]amino}methyl-2-                                          amine      thiophenemethanol, mp 93 - 94° C;                                      nmr (CDCl.sub.3) δ 2.42 (s, 3H),                                        2.8                                                                           (m, 6H), 3.1 (s, 2H), 4.9 (+,                                                 J = 6, 1H), 5.9 (s, 2H), 6.7                                                  (m, 5H); the hydrochloric acid                                                addition salt has mp 183 - 185° C,                                     nmr (DMSO-d.sub.6) δ 2.49 (s, 3H)        19     14           3,4-dimethoxy-                                                                           α -{[(3,4-dimethoxyphenethyl)-                               phenethylamine                                                                           amino]methyl}-5-phenyl-2-thio-                                                phenemethanol; nmr (CDCl.sub.3) δ                                       2.9 (m, 6H), 3.16 (s, 2H), 3.82                                               (s, 6H), 5.0 (m, 1H), 6.75 -                                                  7.7 (m, 10H); corresponding                                                   hydrochloric acid addition salt                                               has mp 185° C (dec)                     20     11           isopropylamine                                                                           5,4-dimethoxy-α-(isopropyl-                                             aminomethyl)-2-thiophenemethanol;                                             mp 74 - 75° C; the hydrochloric                                        acid additon salt has mp 102 -                                                103° C; the corresponding isomer,                                      3,4-dimethoxy-β-(isopropylamino)-                                        2-thiopheneethanol has                                                        bp 110° C/0.5 mm                        21     10           3,4-dimethoxy-                                                                           4,5-dichloro-α-{[(3,4-dimethoxy-                             phenethylamine                                                                           phenethyl)amino]methyl}-2-thio-                                               phenemethanol; γ.sub.max                                                .sup.CHCl.sbsp.3 3600, 1595                                                   1515, 1465 cm.sup.-1 ; the hydrochloric                                       acid addition salt has mp 160 -                                               161° C                                  22     10           2-(indol-3-yl)-                                                                          4,5-dichloro-α-{[(2-indol-3-                                 ethylamine ylethyl)amino]methyl}-2-thio-                                      (tryptamine)                                                                             phenemethanol; mp 43 - 45°  C;                                         the hydrochloric acid addition                                                salt has mp 204 - 205° C                23     10           3,4,5-trimethoxy-                                                                        4,5-dichloro-α-{[(3,4,5-tri-                                 phenethylamine                                                                           methoxyphenethyl)amino]methyl}-                                               2-thiophenemethanol; nmr (CDCl.sub.3)                                         δ 2.75 (m, 6H), 2.90 (s, 2H),                                           3.80 (s,9H), 4.75 (m, 1H),                                                    6.33 (s, 2H), 6.66 (s, 1H); the                                               hydrochloric acid addition salt                                               has mp 167 - 168° C                     24     10           α-[1-(methyl-                                                                      4,5-dichloro-α-{[N-methyl-N-                                 amino)ethyl]-                                                                            β-hydroxy-αmethylphenethyl)-                            benzyl alcohol                                                                           amino]methyl}-2-thiophene-                                         (d,l-ephedrine)                                                                          methanol; nmr (CDCl.sub.3) δ 1.08                                       (d, 3H), 6.60 (s, 1H), 7.30                                                   (s, 5H); the hydrochloric acid                                                addition salt has mp 63 - 65° C         25     10           p-hydroxy- 4,5-dichloro-{[p-hydroxyphen-                                      phenethylamine                                                                           ethyl)amino]methyl}-2-thiophene-                                   (tyramine) methanol; nmr (CDCl.sub.3) δ 2.75                                       (m, 6H), 4.70 (s, 3H), 4.73                                                   (+, 1H); the hydrochloric acid                                                addition salt has mp 180 - 181° C       26     10           p-chloro-  4,5-dichloro-α-{](p-chlorophen-                              phenethylamine                                                                           ethyl)amino]methyl}-2-thio-                                                   phenemethanol; mp 107 - 110° C;                                        the hydrochloric acid addition                                                salt as mp 175 - 176° C                 27     10           p-methyl-  4,5-dichloro-α-{[(p-methyl-                                  phenethylamine                                                                           phenethyl)amino]methyl}-2-                                                    thiophenemethanol; mp 92 -                                                    94° C; the hydrochloric acid                                           addition salt has mp 231° C (dec)       28     10           p-methoxy- 4,5-dichloro-α-{[(p-methoxy-                                 phenethylamine                                                                           phenethyl)amino]methyl}-2-                                                    thiophenemethanol; mp 95 - 100° C;                                     the hydrochloric acid addition                                                salt has mp 202° C                      29     10           1-(p-methoxy-                                                                            α-(4,5-dichloro-2-thienyl)-4-                                phenyl)piperazine                                                                        (p-methoxyphenyl)-1-piper-                                                    azineethanol; mp 126 - 128° C;                                         the dihydrochloric acid                                                       addition salt has mp 213 -                                                    215° C (dec)                            30     10           3,4-(methyl-                                                                             4,5-dichloro-α-{[(3,4-methyl-                                enedioxy)- enedioxy)phenethyl]amino}methyl-                                   phenethylamine                                                                           2-thiophenemethanol; mp 99 -                                                  103°  C; the hydrochloric acid                                         addition salt has mp 215° C (dec)       31     12           isopropyl- 5-chloro-α-[1-(isopropylamino)-                              amine      ethyl]-2-thiophenemethanol;                                                   γ.sub.max .sup.CHCl.sbsp.3 3300,                                        1460, 1145, 1130,                                                             1060, 995 cm.sup.-1 ; the hydrochloric                                        acid addition salt has mp 200° C                                       (dec); two corresponding                                                      isomers, erythro- and threo-5-                                                chloro-β-(isopropylamino)-α-                                       methyl-2-thiopheneethanol have                                                γ.sup.max .sub.CHCl.sbsb.3 3410,                                        1450, 1120, 1060,                                                             990 cm.sup.-1 and γ.sup.max                                             .sub.CHCl.sbsb.3 3400, 1450,                                                  1065, 990 cm.sup.-1, respectively.             __________________________________________________________________________

EXAMPLE 32 N-(3,4-Dimethoxyphenethyl)-β-methoxy-2-thiopheneethylamine(ArCHOR¹ CHR² NR³ R⁴ ; Ar = 2-thienyl, R¹ = CH₃, R² and R³ = H and R⁴ =3,4-dimethoxyphenethyl)

A solution of the halohydrin,α-(bromomethyl)-2-thiophenemethanol (10.0g, 0.048 mole), described in Example 4, and p-toluenesulfonic acid (1.0g) in 100 ml of the lower alkanol methanol, is heated at reflux for 5hr. The mixture is concentrated and the concentrate extracted withether. The ether extract is washed with water and brine, dried (MgSO₄)and concentrated to yield a brown liquid which is purified bychromatography on silica gel to give α-(bromomethyl)-2-thiophenemethanolmethyl ether; nmr (CDCl₃) δ 3.36 (s, 3H), 3.58 (m, 2H), 4.68 (t, J =6.5, 1H), 7.02 (m, 1H), 7.05 (m, 1H), 7.31 (m, 1H).

A solution of the latter compound (15.0 g, 0.068 mole) and the amine,3,4-dimethoxyphenethylamine (18.5 g, 0.102 mole) in 200 ml toluene isheated at reflux for 21 hr. The mixture is cooled to room temperature,shaken with 200 ml 5% NaOH and extracted with chloroform. The combinedorganic extracts are washed with water and brine, dried (K₂ CO₃) andconcentrated to give a brown liquid. The liquid is purified bychromatography to yield the title compound; γ_(max) ^(CHCl).sbsp.3 3290,2980, 2910, 2820, 1510, 1260 cm⁻¹.

The oxalic acid addition salt of the title compound has mp 210° C.

By following the procedure of Example 32 and using the halohydrins, forexample, those described in Examples 4 - 14, together with theappropriate lower alkanol and amine, the corresponding lower alkylethers of the thiophene ethanolamine of this invention are obtained, forexample, the corresponding lower alkyl ethers of the thiopheneethanolamines of Examples 15 - 31.

EXAMPLE 33α-{[N-(3,4-dimethoxyphenethyl)-N-methylamino]methyl}-5-methyl-2-thiophenemethanol(ArCHOR¹ CHR² NR³ R⁴ ; Ar = 5-methyl-2-thienyl, R¹ and R² = H, R³ = CH₃and R⁴ = 3,4-dimethoxyphenethyl)

solution ofα-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol(2.29 g, 0.007 mole, described in Example 16, and the lower alkylhalide, iodomethane (9.94 g, 0.07 mole), in 70 ml benzene is stirred at25° C for 3 days. The mixture is concentrated under reduced pressure.The residual oil is taken up in methanol and made alkaline with 10%NaOH. The mixture is extracted with chloroform. The extract is washedwith water, dried (K₂ CO₃) and concentrated to give a yellow oil, whichis purified by chromatography to give the title compound; nmr (CDCl₃) δ2.41 (s, 3H), 2.46 (s, 3H), 2.6 - 2.8 (m, 6H), 3.68 (s, 1H), 3.83 (s,3H), 3.88 (s, 3H), 4.88 (t, 1H), 6.6 - 6.9 (m, 5H).

The oxalic acid addition salt has mp 149° C.

By following the procedure of Example 33 and using the appropriatesecondary amine, namely a thiophene ethanolamine in which R³ ishydrogen, for example, those described in Example 15 to 23, togetherwith the appropriate lower alkyl halide, the corresponding thiopheneethanolamines in which R³ is lower alkyl are obtained.

EXAMPLE 34 α-(Isopropylaminomethyl)-5-methoxy-2-thiophenemethanol(ArCHOR¹ CHR² NR³ R⁴ : Ar = 5-methoxy-2-thienyl, R¹, R² and R³ = H andR⁴ = isopropyl)

2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF andbutyl lithium (0.135 moles) in hexane is added dropwise. The solution isstirred at room temperature 15 hr and then heated at reflux for 1 hr.After cooling, the clear solution is transferred to a dropping funnel bymeans of a siphon. The solution of thienyl lithium is added dropwise toa solution of diethyl oxalate (19.7 g) in 150 ml THF at -78° C. Afterstirring 2 hr at -78° C, the mixture is brought to -10° C and treatedwith saturated NH₄ Cl solution. The aqueous fraction is separated andextracted several times with ether. The combined ether extracts arewashed with water and brine, dried (MgSO₄) and concentrated.Chromatography on silica gel (eluant = benzene) gives5-methoxy-2-thiopheneglyoxylic acid ethyl ester (2; X¹ = CH₃ O, X² andX³ = H and R¹⁰ = C₂ H₅); mp 136° - 137° C after recrystallization frombenzene-hexane.

The latter ester (25 g) is stirred in 500 ml of 5% aqueous KOH inmethanol (250 ml H₂ O, 250 ml CH₃ OH, 25 g KOH) at room temperature forabout 2 hr. The mixture is diluted with water and extracted severaltimes with ether to remove all neutral material. The aqueous fraction iscooled with crushed ice, acidified with 10% HCl and extracted withether. The ether extract is washed with water and brine, dried (MgSO₄)and concentrated to give 5-methoxy-2-thiopheneglyoxylic acid (3; X¹ =CH₃ O, X² and X³ = H and R¹⁰ = H); γ_(max) ^(CHCl).sbsp.3 3000, 1630,1625, 1530 cm⁻¹.

The latter acid (14.0 g) and triethylamine (i.1 g) are dissolved in 100ml anhydrous THF and cooled to 0° C under a nitrogen atmosphere. Methylchloroformate (8.5 g) in 5 ml THF is added dropwise and the solution isstirred for 2 hr at 0° C. After this time, isopropylamine (30 ml) isadded dropwise and the solution is again stirred for 2 hr at 0° C. Thereaction mixture is then poured onto water, separated and the aqueousfraction is extracted several times with ether. The ether fractions arewashed with water and brine, dried (MgSO₄) and concentrated. The crudeproduct is subject to chromatography on silica gel (750 g, benzeneethylacetate, 95:5). Evaporation of the eluate and recrystallization of theresidue from hexane-benzene givesN-isopropyl-5-methoxy-2-thiopheneglyoxylamide; mp 72° -73° C.

To freshly distilled boron trifluoride etherate (61.0 mmoles) dissolvedin 30 ml anhydrous ether, distilled epichlorohydrin (4.19 g, 46.0mmoles) is added at such a rate to cause the solution to reflux. Afteraddition, the solution is heated at reflux for 1.5 hr with vigorousstirring. The reaction mixture is cooled and most of the ether isremoved with a pipette and the solid residue is dried with a stream ofdry nitrogen. Anhydrous methylene chloride (50 ml) and theN-isopropyl-5-methoxy-2-thiopheneglyoxylamide (8.0 g, 39.0 mmole),described above, is added and the solution is stirred at roomtemperature for 56 hr. The methylene chloride is evaporated and replacedwith 50 ml anhydrous methanol. The solution is cooled to 0° C. andsodium borohydride (4.0 g) is added portionwise over a period of 4 hr.The mixture is brought to room temperature, stirred for 24 hr thenquenched with ice-water. The aqueous solution is extracted several timeswith ether. The combined ether extract are washed with water and brine,dried (MgSO₄) and concentrated. The product is purified bychromatography on silica gel (400 g, chloroformmethanol, 8:2).Evaporation of the eluate and recrystallization of the residue fromhexane gives the title compound; mp 81° C, γ_(max) ^(CHCl).sbsp.3 3300,3100, 1650, 1505, 1220 cm⁻¹.

The oxalic acid addition salt of the title compound has mp 100° - 101°C.

We claim:
 1. A compound of the formula

    ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4

in which Ar is selected from the group consisting of 2-thienyl, 5-(lower alkyl)-2-thienyl, 5-phenyl-2-thienyl and 4,5-dichloro-2-thienyl; R¹ is hydrogen or lower alkyl; R² is hydrogen or lower alkyl; R³ and R⁴ together with the nitrogen to which they are joined form a 4-(4-methoxyphenyl)-or 4-(o-tolyl)piperazin-1-yl group, or the acid addition salts thereof with pharmaceutically acceptable acids.
 2. α-(2-Thienyl)-4-(o-tolyl-1-piperazineethanol, as claimed in claim
 1. 3. α-(2-Thienyl-4-(o-tolyl-1-piperazineethanol hydrochloride, as claimed in claim
 1. 4. α-(4,5-Dichloro-2-thienyl)-4-(p-methoxyphenyl)-1-piperazineethanol, as claimed in claim
 1. 5. α-(4,5-Dichloro-2-thienyl)-4-(p-methoxyphenyl-1-piperazineethanol dihydrochloride, as claimed in claim
 1. 6. A compound of formula

    ArCHOR.sup.1 CHR.sup.2 NR.sup.3 R.sup.4

in which Ar is selected from the group consisting of 2-thienyl, 5-methyl-2-thienyl, 5-phenyl-2-thienyl and 4,5-dichloro-2-thienyl; R¹ is hydrogen or methyl; R² is hydrogen; R³ and R⁴ together with the nitrogen to which they are joined form a 4-(4-methoxyphenyl)- or 4-(o-tolyl)-piperazin-1-yl group; or the acid addition salts thereof with pharmaceutically acceptable acids, as claimed in claim
 1. 